chrX-70035527-T-C

Variant names:

• chrX-70035527-T-C
• rs397516654
• NM_001399.5:c.1094T>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 17P and 4B. PS3 PM1 PM5 PP2 PP5_Very_Strong BS2

The NM_001399.5(EDA):​c.1094T>C​(p.Val365Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000431 in 1,205,588 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000060818: Functional studies suggest that the Val365Arg variant may affect cell signaling pathways, but does not show the same decrease in receptor binding seen in classic HED variants (Mues 2010)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V365M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000045 (0 hom. 13 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 4.35
• Publications: 2 publications found

Genes affected

EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EDA Gene-Disease associations (from GenCC):

• tooth agenesis, selective, X-linked, 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000060818: Functional studies suggest that the Val365Arg variant may affect cell signaling pathways, but does not show the same decrease in receptor binding seen in classic HED variants (Mues 2010).; SCV000630019: Experimental studies have shown that this missense change affects EDA function (PMID: 19623212).; SCV001805476: Published functional studies demonstrate a damaging effect with reduced receptor binding and signaling capability compared to wildtype (Mues et al., 2010);; SCV004239086: in vitro experimental studies demonstrate that the signaling capacity of protein constructs containing p.Val365Ala are impaired even though cellular production, export and receptor binding are readily detectable.; SCV004046192: Functional studies suggest that the c.1094T>C (p.Val365Ala) variant may affect cell signaling pathways (PMID: 19623212).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_001399.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70035526-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1482275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked hypohidrotic ectodermal dysplasia, tooth agenesis, selective, X-linked, 1, tooth agenesis.
• PP5: Variant X-70035527-T-C is Pathogenic according to our data. Variant chrX-70035527-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 49 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	NM_001399.5	MANE Select	c.1094T>C	p.Val365Ala	missense	Exon 8 of 8	NP_001390.1	Q92838-1
	EDA	NM_001005609.2		c.1088T>C	p.Val363Ala	missense	Exon 8 of 8	NP_001005609.1	Q92838-3
	EDA	NM_001440761.1		c.1085T>C	p.Val362Ala	missense	Exon 8 of 8	NP_001427690.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	ENST00000374552.9	TSL:1 MANE Select	c.1094T>C	p.Val365Ala	missense	Exon 8 of 8	ENSP00000363680.4	Q92838-1
	EDA	ENST00000374553.6	TSL:1	c.1088T>C	p.Val363Ala	missense	Exon 8 of 8	ENSP00000363681.2	Q92838-3
	EDA	ENST00000524573.5	TSL:1	c.1079T>C	p.Val360Ala	missense	Exon 8 of 8	ENSP00000432585.1	Q92838-9

Frequencies

GnomAD3 genomes AF: 0.0000279 AC: 3 AN: 107573 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000575

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182595 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000446 AC: 49 AN: 1098015 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 13 AN XY: 363371

African (AFR) AF: 0.0000379 AC: 1 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000558 AC: 47 AN: 841954

Other (OTH) AF: 0.0000217 AC: 1 AN: 46094

GnomAD4 genome AF: 0.0000279 AC: 3 AN: 107573 Hom.: 0 Cov.: 21 AF XY: 0.0000334 AC XY: 1 AN XY: 29983

African (AFR) AF: 0.00 AC: 0 AN: 29419

American (AMR) AF: 0.00 AC: 0 AN: 9807

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2581

East Asian (EAS) AF: 0.00 AC: 0 AN: 3420

South Asian (SAS) AF: 0.00 AC: 0 AN: 2349

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5501

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000575 AC: 3 AN: 52170

Other (OTH) AF: 0.00 AC: 0 AN: 1422

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	EDA-related disorder (1)
1	-	-	Hypodontia (1)
1	-	-	Hypohidrotic X-linked ectodermal dysplasia (2)
1	-	-	Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	Tooth agenesis, selective, X-linked, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.35	N
PhyloP100		4.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.52	N
REVEL	Pathogenic	0.67
Sift	Benign	0.047	D
Sift4G	Benign	0.087	T
Polyphen		0.39	B
Vest4		0.16
MVP		1.0
MPC		1.1
ClinPred		0.46	T
GERP RS		5.4
Varity_R		0.83
gMVP		0.89
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516654; hg19: chrX-69255377;